1. Field of the Invention
This invention relates to new organic compounds and, more particularly, is concerned with novel polymeric 1,4-bis-[(cyclic-substituted)alkylamino]anthraquinone, anthrapyrazole, aza-anthraquinone and diaza-anthraquinone compounds which are active as anticancer agents and inhibit tumor growth in a mammal.
More particularly, the invention relates to the preparation and use of copolymers which are synthesized from anthraquinone, anthrapyrazole, aza-anthraquinone and diaza-anthraquinone monomers copolymerized with another monomer, namely, a dianhydride molecule.
2. Description of the Related Art
Macromolecules have been used as drug carriers in an attempt to prolong plasma levels of drugs presumably through slow release of drugs from macromolecules, and to achieve favorable uptake by the tumor cells. Among macromolecular carriers, divinyl ethermaleic anhydride (MVE) copolymer has been investigated extensively. MVE copolymer contains multiple anhydride rings, which allow easy functionalization with antitumor agents carrying nucleophilic groups such as -NH.sub.2, -OH, and -SH. Furthermore, a carboxyl group is generated when each anhydride ring is functionalized with a drug molecule. Therefore, MVE copolymer is capable of covalently binding a large number of lipophilic antitumor agents, while maintaining water solubility.
MVE copolymer has been linked covalently with various therapeutically active antitumor agents including 5-fluorouridine, daunomycin, adriamycin, .beta.-D-arabinofuranosylcytosine and methotrexate with varying results. Some of the MVE-linked agents demonstrated higher therapeutic efficacies and lower toxicities during in vivo antitumor evaluations while others showed no increase in efficacy relative to the parent drugs.
U.S. Pat. No. 4,520,162 discloses that MVE copolymer linked with adriamycin showed significantly higher therapeutic efficacies and lower toxicities than adriamycin, whereas daunomycin conjugated with MVE copolymer gave only marginal benefit than daunomycin. Also, attachment of MVE copolymer to a different site on the same antitumor drug yields conjugates with different antitumor activity. For example, adriamycin conjugated to MVE copolymer via amide linkages (U.S. Pat. No. 4,520,162) shows higher antitumor activity than the corresponding conjugate via ester linkages (Belgian Patent 902,344). Furthermore, U.S. Pat. No. 4,520,162 demonstrated that different degree of drug conjugation (i.e., arabinofuranosylcytosine) also gives different effect on the antitumor activity.
The anthraquinones, anthrapyrazoles, aza-anthraquinones and diaza-anthraquinones useful in this invention are a group of compounds having an anthracene moiety of which mitoxantrone is a representative member. Mitoxantrone is indicated for treatment of acute nonlymphocytic leukemia, and breast tumors (in Canada and other countries, but not the U.S.) in humans. While these agents exhibit excellent antitumor activity, they also exhibit toxicity to normal cells. For example, administration of mitoxantrone is associated with myelosuppression as well as other side effects.
In one copending application, Ser. No. 037,149, filed Mar. 25, 1993, synthetic anthracene antineoplastic compounds are covalently conjugated with, or in admixture with, a hydrolyzate of a co-polymeric moiety of divinyl ether and maleic anhydride (MVE) and show higher antitumor activity than either agent exhibits when administered alone.
U.S. Pat. No. 4,526,788 describes novel polymeric 1,4-bis-[(1,3-oxazolidin-3-yl)alkylamino]anthraquinones prepared by condensation of 1,4-bis-[(2-hydroxyalkylamino)alkylamino]anthraquinones with dialdehydes which are useful as anticancer agents. However, this series of polymers is not water-soluble. The polymer has to be administered to mammals intraperitoneally as a suspension. Furthermore, this series of polymers is only tested against lymphocytic leukemia P388 and melanotic melanoma B16 in mammals.
The present invention provides a method to prepare water-soluble polymers allowing easy administration by intravenous route in addition to intraperitoneous route. These novel polymers potentiate the antitumor activity of anthraquinones, anthrapyrazoles, aza-anthraquinones and diaza-anthraquinones. In comparison with the parent drug, the polymers have higher antitumor activities and better therapeutic index against not only P388 leukemia, but also some solid tumors in mammals.